| Summary: | Background and objective Pirfenidone is an antifibrotic agent that has been proven to slow down the progression of idiopathic pulmonary fibrosis (IPF). This study aimed to characterize the population pharmacokinetics (PK) and exposure–efficacy analysis of pirfenidone in patients with IPF. Methods Data from 10 hospitals with 106 patients were used to develop a population PK model. The annual decline in forced vital capacity (FVC) over 52 weeks was integrated with pirfenidone plasma concentration to characterize the exposure–efficacy relationship. Results A linear one-compartment model with first-order absorption and elimination processes and lag time best described the pirfenidone PK. The population estimates of clearance and central volume of distribution at steady-state were 13.37 L/h and 53.62 L, respectively. Bodyweight and food were statistically correlated with PK variability but had no significant influence on pirfenidone exposure. Annual decline in FVC with pirfenidone plasma concentration was described by a maximum drug effect (Emax) model. The typical $ EC_{50} $ was 1.73 mg/L (1.18–2.31 mg/L) and the corresponding $ EC_{80} $ was 2.18 mg/L (1.49–2.87 mg/L). Simulations showed that two dosing regimens of 500 and 600 mg three times daily were predicted to generate 80% of the Emax. Conclusions In patients with IPF, covariates such as bodyweight and food might not be sufficient for dose adjustment, and a low dose of 1500 mg/day could also provide 80% of the Emax, as the standard dose (1800 mg/day).
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